Until recently, the Unmethlyated, long CGG repeat track in the FMR1 5'UTR was thought to have little or no phenotype consequence. Now, it is well established that this expanded repeat track leads to an increased risk for premature ovarian failure (POP) among women who carry the premutation (55-199 repeats) and an increased risk for a late-onset tremor/ataxia syndrome (FXTAS), primarily among men with the premutation. We hypothesize that the high repeat tract in the FMR1 gene increases the risk for these age-related disorders through a dominant negative toxic effect of the FMR1 transcript. The goal of this study is to identify the full phenotypic spectrum of the high repeat track alleles of the FMR1 gene among adult carriers and to elucidate the risk factors associated with phenotype expression. In previous grant period, we established an infrastructure to identify individuals from the general population and from families with fragile X syndrome (FXS) who carry high repeat alleles. Our results suggest that the increased risk is primarily associated with premutation allele carriers. Thus, in this re-submission, we will focus on ascertaining all first-degree relatives of premutation carriers-all subjects will be ascertained in a systematic manner to reduce the bias in estimates of relative risk and penetrance among repeat size groups. We will test the hypothesis that the FMR1 repeat length is a QTL that influences an individual's pattern of relative strengths and weaknesses within their neuropsychological functioning, but is generally not associated with clinical problems. We will also test the hypothesis that there are age-dependent, presymptomatic signs related to FXTAS that can be identified among premutation carriers. We will establish quantitative parameters that can be tracked over time to examine the natural history of FXTAS and determine if other health factors are associated with onset, progression and severity of symptoms. These studies will begin to unravel one aspect of the complex pathways related to neuropsychological function and age-associated neurological and cognitive decline.